The role of children in transmission of SARS-CoV-2 variants of concern within households: an updated systematic review and meta-analysis, as at 30 June 2022

Background Meta-analyses and single-site studies have established that children are less infectious than adults within a household when positive for ancestral SARS-CoV-2. In addition, children appear less susceptible to infection when exposed to ancestral SARS-CoV-2 within a household. The emergence of SARS-CoV-2 variants of concern (VOC) has been associated with an increased number of paediatric infections worldwide. However, the role of children in the household transmission of VOC, relative to the ancestral virus, remains unclear. Aim We aimed to evaluate children's role in household transmission of SARS-CoV-2 VOC. Methods We perform a meta-analysis of the role of children in household transmission of both ancestral SARS-CoV-2 and SARS-CoV-2 VOC. Results Unlike with the ancestral virus, children infected with VOC spread SARS-CoV-2 to an equivalent number of household contacts as infected adults and were equally as likely to acquire SARS-CoV-2 VOC from an infected family member. Interestingly, the same was observed when unvaccinated children exposed to VOC were compared with unvaccinated adults exposed to VOC. Conclusions These data suggest that the emergence of VOC was associated with a fundamental shift in the epidemiology of SARS-CoV-2. It is unlikely that this is solely the result of age-dependent differences in vaccination during the VOC period and may instead reflect virus evolution over the course of the pandemic.


Introduction
In the first 6 months of the COVID-19 pandemic, numerous household transmission studies suggested that compared with adults, children were less susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and less likely to transmit the virus [1]. These findings were echoed in studies outside of households where the infection rate of SARS-CoV-2 among children younger than 10 years was significantly lower than that of adults [2]. However, since August 2020, the continuous emergence of new variants of SARS-CoV-2 has raised questions as to whether there has been a fundamental shift in the epidemiology of SARS-CoV-2 [3,4].
Globally, there have been at least three peaks corresponding to the circulation of variants of concern (VOC) Alpha (Phylogenetic Assignment of Named Global Outbreak (Pango) lineage designation B.1.1.7) (or Beta (B.1.351)/Gamma (P.1)), of Delta (B.1.617.2) and of Omicron (B.1.1.529) [3,5]. During these waves, there has been speculation that children have become more susceptible to SARS-CoV-2 infection and more infectious once they contracted the virus. For example, during the Delta wave in Singapore, children (aged 0-11 years) were significantly more likely to transmit and acquire SARS-CoV-2 in a household compared with young adults (18-29 years) [6]. Similarly, during the Omicron wave in the United States (US), the secondary attack rates (SAR) were consistently high across household contact and index age groups, including those aged 0-4 years [7].
Despite these single-site studies, meta-analysis of the role of children in the spread of VOC (relative to the ancestral virus) are generally lacking, with studies often focused on the ancestral virus [8] or not differentiating between data collected during the pre-VOC and VOC-dominant period [9]. Where pre-VOC-and VOCbased studies have been differentiated, data suggest an increased role for children in the household transmission of VOC [8]. However, such analysis remains confounded by the fact that globally, adults have been prioritised for vaccination [10]. Vaccination campaigns for COVID-19 were largely rolled out from December 2020 onwards but with a primary focus on vaccinating individuals 18 years and older. The European Medicines Agency did not approve the vaccination of children 5-11 years of age until November 2021 [11]. Furthermore, paediatric vaccination rates remain consistently lower than those of adults [12]. Vaccination has been shown to reduce the household transmission of SARS-CoV-2 substantially [13]. As a result, it is difficult to ascertain if any observed epidemiological changes in the demographics of viral transmission over time have resulted from a fundamental change in the virus over time or if a potential increase in paediatric infections and transmission is simply indicative of the lower vaccination rate among children.
To assess what effect the SARS-CoV-2 VOC have on children in terms of infectiousness and susceptibility to SARS-CoV-2 infection within a household, we here performed a meta-analysis comparing paediatric SARS-CoV-2 transmission during the pre-VOC-and VOC-dominant period.

Methods
To use newly published data to further the understanding of the role of children in the household transmission of both ancestral SARS-CoV-2 and SARS-CoV-2 VOC, this systematic review and meta-analysis was performed covering studies published between 25 August 2020 and 30 June 2022.

Case definitions
We adapted the World Health Organization household transmission investigation protocol for COVID-19 [14]. A household was defined as a group of people (two or more) living in the same residence. Household PRISMA flow diagram, systematic review of the role of children in transmission of SARS-CoV-2 variants of concern within households, 25 Table a Characteristics of new studies included in the present meta-analysis on the role of children in transmission of SARS-CoV-2 variants of concern within households, 25 August 2020-30 June 2022 (n = 48)

Table b
Characteristics of new studies included in the present meta-analysis on the role of children in transmission of SARS-CoV-2 variants of concern within households, 25 August 2020-30 June 2022 (n = 48)

Table e
Characteristics of new studies included in the present meta-analysis on the role of children in transmission of SARS-CoV-2 variants of concern within households, 25 August 2020-30 June 2022 (n = 48) transmission was defined as two or more positive SARS-CoV-2 cases that occurred in a household within the follow-up period of 28 days after identifying the index. An index case was defined as the first case of laboratory-confirmed COVID-19 in the same household. A secondary case was defined as a known household contact of the index case who tested positive for SARS-CoV-2 during the follow-up period. A household contact was defined as a person who has cohabited with the index case in the same household during the 28 days. In this context, the SAR measured the frequency of secondary infections of COVID-19 among household contacts in a defined period of time, as determined by a positive COVID-19 result. Adults were defined as individuals 18 years and older, while children were defined as individuals younger than 18 years.

Classification of SARS-CoV-2 variants of concern by study period
Studies were classified as pertaining to the ancestral virus or a VOC based on available genotype data and/ or the timing of the study period. Specifically, studies where SARS-CoV-2 genotype was not documented and the index case identification period was before 1 January 2021 were defined as pertaining to data from the period of ancestral virus predominance (pre-VOC period). Studies where data were collected between 1 January 2021 and 30 June 2022 were categorised as pertaining to the VOC period.

Vaccination status
In investigating the effect of vaccination on transmission, only studies reporting vaccination status of household contacts were included. Vaccinated individuals were defined as those who had received at least one dose of a SARS-CoV-2 vaccine.

Search strategy and eligibility criteria
The literature search was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [15]. Our original systematic review had screened literature from 1 December 2019 to 24 August 2020 [1], therefore in this study, publications available between 25 August 2020 and 30 June 2022, were accessed from PubMed, Covid MEDLINE, Embase and Web of Science, using the search term: ("COVID-19" OR "SARS-CoV-2" OR "variant") AND ("household transmission" OR "family cluster" OR "household contact") OR ("transmissibility" OR "attack rate") OR ("vaccination" OR "attack rate") with no language or location restrictions. Given the role of preprints in timely dissemination of research findings during the COVID-19 pandemic, we also conducted searches of the medRxiv and bioRxiv servers using the search term ("COVID-19" OR "SARS-CoV-2") AND ("household transmission" OR "secondary attack rate") for the posted articles. The Strengthening the Reporting of Observational studies in Epidemiology (STROBE) checklists was applied to evaluate the quality of the literature. Investigator YZ developed the initial search strategy, and two researchers (YZ and XY) performed a primary search simultaneously. In cases of difference in opinion, they referred to the selection protocol. If the dispute remained, a third individual (JP or KS) made the final decision. Studies that were duplicate publications, modelling studies, case reports, serological studies and/or reviews were excluded due to a lack of sufficient and/or appropriate data ( Figure  1).

Statistical analysis
We assessed the infectiousness and susceptibility of children and adults to SARS-CoV-2 infection during different time periods by pooling all data deemed eligible by the above selection criteria. Susceptibility to SARS-CoV-2 VOC infection was estimated by pooling the SAR for household contacts. We estimated the relative risk (RR) for SARS-CoV-2 household secondary infection stratified by the age of index cases, the age of household contacts and the vaccination status of household contacts for each study. We then used generalised linear mixed models [16] to estimate pooled RR along with corresponding 95% confidence intervals (CI). As only observational studies were included, we used a random effects model, equalising the weight of the studies to the pooled estimate. Where relevant, we stratified the analysis by pre-specified characteristics including the characteristics of index cases and contacts. A random effects model was used to test subgroup differences. Heterogeneity between studies was evaluated using the I 2 statistic test. A threshold of I 2 > 50% indicated statistically significant heterogeneity. All summary analyses and meta-analysis were performed using R studio software (version 3.6.1).

Infectiousness of children with SARS-CoV-2 within households during the period when the ancestral virus was dominant
Fourteen studies were identified that defined the age of the index case and the SAR in the household during the time period in which the ancestral virus was dominant (until 1 January 2021). Another 14 studies were identified that defined the age of the index case and the SAR in the household during the time period in which VOC were dominant. An increasing trend of estimated SAR over time is shown in Figure 2. During the time period when the ancestral virus was dominant (before 1 January 2021), a paediatric index case was associated with a significantly lower SAR compared with an adult index case (RR = 0.61; 95% CI: 0.47-0.80). In contrast, there was no significant difference in SAR (RR = 0.98; 95% CI: 0.85-1.13) between a paediatric index case and an adult index case during the VOC-dominant period. The detailed RR data for the secondary attack rate among household members, when either an adult or a child was identified as the index case, is available in Supplementary Figure S2. The role of children under 12 years in transmitting a VOC within the household was examined by eight observational studies which involved paediatric index cases of different ages with no significant heterogeneity (I 2 = 19%, p = 0.29). The SAR caused by young paediatric index cases (< 12 years) during the VOC period were higher than SAR attributable to older paediatric index cases (≥ 12 years), in whom we found an estimated 46% significant increase in SAR among household contacts. Supplementary Figure S3 contains a meta-analysis of the SAR among household members, considering both younger and older children as the index case. Taken together, these data suggest that during the period of VOC dominance, children, especially children under 12, were more infectious within households than during the period when the ancestral virus was predominant.

Secondary attack rate of children in household transmission of SARS-CoV-2 during the circulation of variants of concern
To determine the susceptibility of children to household SARS-CoV-2 infections, the SAR in the household contacts was assessed in 29 pre-VOC studies and 22 VOC studies. The increasing trends of SAR among Each time point is based on the midpoint of the study period in each study. Multi-VOC points represent studies with two or more predominant variants. Lines: the smoothed curve of secondary attack rates by month for each group; shaded bands: 95% confidence intervals. Each time point is based on the midpoint of the study period in each study. Multi-VOC points represent studies with two or more predominant variants. Lines in panel A: smoothed curves of secondary attack rates by month for each group; shaded bands: 95% confidence intervals.
child and adult contacts in household SARS-CoV-2 transmission was associated with the growing dominance of SARS-CoV-2 VOC since 2021 (Figure 3). The random effects model suggests that children were statistically less likely to acquire ancestral SARS-CoV-2 (SAR = 0.18, 95% CI: 0.12-0.26) than VOC (SAR = 0.31, 95% CI: 0.24-0.38). The raw data used to estimate the pooled SAR of children contacts in household SARS-CoV-2 transmission, stratified by the pre-VOC and VOC period, are available in Supplementary Figure S4. The test of subgroup difference showed there was a statistically significant subgroup effect (p < 0.01). In contrast, before VOC were dominant, the average pooled SAR of adults (SAR = 0.29, 95% CI: 0.23-0.39) was similar to those during the VOC period (SAR = 0.31, 95% CI: 0.26-0.37; p = 0.64). We provide the detailed results on household SAR of adult contacts stratified by the pre-VOC and VOC period in Supplementary Figure S5. As shown in Figure 3B, household SAR among paediatric contacts for VOC were statistically higher than for the ancestral virus (p < 0.001) and equivalent to those among their adult family members (p = 0.93).
Although we observed significant heterogeneity between the included studies, in a subset analysis where additional information was provided on the age of the paediatric contacts, younger children (< 12 years) were no more or less susceptible to infection than older children (≥ 12 years) during the pre-VOC period (RR = 0.77; 95% CI: 0.59-1.02) (Figure 4). This is consistent with our prior analysis of the SAR in children and adults during the first year of the COVID-19 pandemic [1]. However, the period of VOC shows a different scenario, in which there was an estimated 46% statistically significant increase in SAR among younger paediatric household contacts compared with older children (RR = 1.46; 95% CI: 1.10-1.94) (Figure 4). In addition, our findings show that compared with older children, the estimated risk of younger children acquiring SARS-CoV-2 was significantly different in the two periods (p < 0.01), although the heterogeneity among the observational studies during the VOC period was high (I 2 = 97%, p < 0.01).
The above studies were classified as analysing the pre-VOC and VOC periods based on the time when the data were collected. To confirm that the results were the same when specific virus genotyping was performed, we repeated the analysis with a subset of studies where the specific VOC was determined. Consistent with our prior results [1], children were significantly less likely to acquire the ancestral virus in the household compared with adults. We provide extra RR results for the household transmission of SARS-CoV-2 Alpha, Delta, multi-VOC or Omicron, in comparison to the pre-VOC period in Supplementary Figure S6. In contrast, the risk of children being infected with the Alpha, Delta or Omicron variants was not significantly different from exposed adult household contacts when we analysed the RR of SAR among child and adult contacts; the detailed RR results of this analysis can be viewed in Supplementary Figure S6.
The above data suggest that children were more infectious ( Figure 2) and more susceptible to infection (Figure 3) during the period when VOC were dominant. The household SAR of child contacts stratified by the pre-VOC and VOC period are additionally appended in Supplementary Figure S4. However, this was also the period during which vaccination among adults became widespread. To determine if age-dependent differences in vaccination affected these data, we examined (during the VOC period only) SAR by vaccination status of household contacts regardless of vaccination status or age of the index cases. Only nine studies from Denmark, Israel, Japan, the Netherlands, Norway, Singapore, the UK and the US reported the effectiveness of vaccination against secondary transmission of SARS-CoV-2 within the household. The estimated SAR was higher for unvaccinated adult contacts than vaccinated adults (RR = 1.78; 95% CI: 1.49-2.13) with heterogeneity (I 2 = 78%, p < 0.01) ( Figure 5). These data demonstrate that vaccination can affect SAR within the household.
To address this issue in the context of age-dependent differences in vaccination and transmission, we analysed a subset of studies that investigated the SAR in unvaccinated children and unvaccinated adults during the period of VOC dominance. In the absence of vaccination there was no difference in the SAR between adults and children (RR = 0.91; 95% CI: 0.78-1.07) ( Figure 5). This is consistent with our prior analysis [1] of the SAR in children and adults. Supplementary Figure S6 contains additional RR results of SAR among child and adult contacts in household transmission of SARS-CoV-2 Alpha, Delta, multi-VOC or Omicron, in comparison to the pre-VOC period.

Discussion
In the early stages of the COVID-19 pandemic, children did not appear to play a significant role in the household transmission of SARS-CoV-2 [1]. Data presented here suggest that this has shifted throughout the course of the pandemic and in particular since the emergence of VOC in the community.
The increased role of children in the household transmission of SARS-Cov-2 during the VOC period adds weight to the importance of COVID-19 vaccination programmes in children, including vaccines now available for those younger than 5 years. This remains a contested issue and many parents find it difficult, in light of the typically mild disease children experience when infected with SARS-CoV-2, to make an informed risk-benefit assessment regarding paediatric vaccination [73]. While the slower rollout or even some differing vaccination recommendations [74] for paediatric COVID-19 vaccination have precluded detailed assessments of the precise effect of paediatric vaccination on household SARS-CoV-2 transmission, it is promising that vaccination reduced the risk of infection among cohabitating adults and teenagers [52] and that the probability of person-to-person SARS-CoV-2 transmission between two vaccinated adults and/or teenagers was 4% (compared with the 61% observed between unvaccinated household members) [52]. These data suggest that paediatric COVID-19 vaccination during the VOC period will not only reduce the risk of severe disease in the child but may also play an important role in reducing household transmission of the virus (most probably for a finite period of time after vaccination).
It remains to be determined if the data shown herein can be translated to scenarios outside the home (e.g. SARS-CoV-2 transmission in the school settings).
However, even if this should be the case, it is important not to interpret these data as a rationale for reintroducing school closures. In contrast to the early stages of the COVID-19 pandemic, high vaccination rates in adults and the increased availability of paediatric vaccination, combined with a global decline in the severity of COVID-19 cases and improved disease

Figure 4
Relative risk for the secondary attack rate of younger and older children contacts in household SARS- Cases describe the number of SARS-CoV-2-positive individuals identified in the study.
prevention measures (e.g. ventilation, mask use) represent an opportunity for continued face-to-face schooling. However, it is clear that public health decisions such as these need to be derived from data on the current circulating SARS-CoV-2 variants, and not the ancestral virus, to most accurately represent the present situation. Prioritising business as usual for all domains of society and layering public health measures on top of these has become operational in most countries learning to live with COVID-19, and these household transmission data add weight to the importance of this. While children have long been thought to be vectors of high viral transmission, e.g. in the case of influenza virus, SARS-CoV-2 still does not follow this trend. Children are just as likely as adults in the VOC era to transmit SARS-CoV-2, but, in contrast to the seasonal influenza patterns, no more likely than adults [75,76]. In terms of differential infectivity of paediatric age groups, our results also imply that the proportion of transmission that occurs between household members and potentially paediatric age-specific risks could differ in future stages of the pandemic, which is informative for infection prevention within households, as well as schools and childcare.
This study has also provided a new insight into the possible causes of increased VOC transmission among children relative to the ancestral virus. Specifically, our study, in addition to one prior meta-analysis [8], suggests that the role of children in household transmission of SARS-CoV-2 has increased during the VOC-dominant period. It is possible that these data represent differential COVID-19 vaccination rates between children and adults, given the role that vaccination can play in preventing the household transmission of SARS-CoV-2 [13]. However, such a hypothesis would suggest that comparing household transmission among unvaccinated adults and children during

Figure 5
Relative risk for the secondary attack rates of child and adult contacts in household SARS-CoV-2 variant of concern transmission stratified by vaccination status Cases describe the number of SARS-CoV-2-positive individuals identified in the study. Vaccinated adults were defined as having received at least one dose of vaccine.
the VOC period would show a pattern akin to that of the ancestral virus (i.e. an age-dependence difference in susceptibility to infection and infectiousness within a household). Instead, we have provided valuable evidence that during the VOC period, there were no age-dependent differences in household SARS-CoV-2 transmission among unvaccinated individuals. These data are consistent with a minimal role of differing adult and paediatric vaccination strategies in the changing epidemiology of SARS-CoV-2 during the pandemic. Instead, these data may suggest that the evolution of the virus over time has resulted in an increased role for children in viral transmissions. Indeed, we have recently shown that the ancestral SARS-CoV-2, but not the Omicron variant, is less efficient at replicating in the primary nasal epithelial cells of children, which may have implications for how much virus a child vs an adult shed within the household [77]. However, it does remain possible that the observed shifts in the epidemiology of SARS-CoV-2 over time represent changes in the virus in addition to age-dependent differences in both vaccination and infection. This represents an important area of ongoing research.
This study was subject to several limitations. A high heterogeneity (I 2 ) was identified in the data. This is probably attributable to variability in study definitions of index cases and household contacts, frequency and type of testing (we were limited by the information provided in the methods section of each of article), sociodemographic factors, household characteristics (e.g. air ventilation), location of study and local policies (e.g. isolation and quarantine). The often mild nature of SARS-CoV-2 infection in children may have meant that the SAR in transmission studies were underestimated. Alternatively, ongoing exposure from the community (rather than within the household) may have led to overestimating transmission in household settings. Only a limited number of studies were available in the VOC period that documented household SARS-CoV-2 transmission among unvaccinated adults and children, and the definition that those having received one dose of a COVID-19 vaccine were considered vaccinated may have an impact on the findings. Furthermore, the exclusion of prior vaccination but not of prior infection might also have influenced the risk of SARS-CoV-2 infection. Nevertheless, the data provide a comprehensive insight into the shifting role of children in virus transmission over the course of the SARS-CoV-2 pandemic.

Conclusions
These findings will inform public health strategies and our response to the ongoing emergence of SARS-CoV-2 variants. Specifically, the increased role of children in the household transmission of SARS-CoV-2 during the VOC period adds weight to the importance of COVID-19 vaccination in children. This may also assist parents' risk-benefit assessment regarding paediatric vaccination, where the benefits can include reducing the household transmission of SARS-CoV-2. In addition, this study has provided a new insight into the possible causes of increased VOC transmission among children relative to the ancestral virus.

Ethical statement
Ethical approval was not needed for this systematic review and meta-analysis.

Funding statement
This work is supported by the National Health and Medical Research Council investigator grant 2007919 to K.R.S.